Person: AKDEMİR, ATİLLA
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Publication Metadata only Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.(2012-10-01) THOMPSON, AJ; de, Graaf; Akdemir, ATİLLA; de, Esch; KOOISTRA, AJ; EDINK, E; LUMMIS, SC; AKDEMİR, ATİLLAA hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [(3)H]epibatidine on chimeric α7/5-HT(3) receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.Publication Metadata only Exploring new Probenecid-based carbonic anhydrase inhibitors: Synthesis, biological evaluation and docking studies.(2015-09-01) MOLLICA, A; COSTANTE, R; Akdemir, ATİLLA; CARRADORI, S; STEFANUCCI, A; MACEDONIO, G; CERUSO, M; SUPURAN, CT; AKDEMİR, ATİLLAPublication Open Access Novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors.(2018-12-01) DEMIR, K; Akdemir, ATİLLA; ANGELI, A; GÜZEL-AKDEMIR, Ö; SUPURAN, CT; AKDEMİR, ATİLLAA small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 lM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors.Publication Metadata only Computer Aided Design and Synthesis of New Ursane Triterpenoids with Nuclear Factor Kappa B Inhibition Effect(2019-12-19) Şenol, Halil; Akdemir, Atilla; Topçu, Gülaçtı; ŞENOL, HALIL; AKDEMİR, ATİLLA; TOPÇU, GÜLAÇTIPublication Open Access Fibrate-based N-acylsulphonamides targeting carbonic anhydrases: synthesis, biochemical evaluation, and docking studies.(2019-12-01) GIAMPIETRO, L; AMMAZZALORSO, A; CARRADORI, S; ANGELI, A; De, Filippis; FANTACUZZI, M; MACCALLINI, C; Akdemir, ATİLLA; SUPURAN, CT; AMOROSO, R; AKDEMİR, ATİLLAA large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Ca carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.Publication Open Access Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII(2019-05-01) Demir-Yazici, Kubra; BUA, Silvia; Akgunes, Nurgul Mutlu; Akdemir, ATİLLA; Supuran, Claudiu T.; Guzel-Akdemir, Ozlen; AKDEMİR, ATİLLANovel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1Hindole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites.Publication Open Access Novel 2-indolinones containing a sulfonamide moiety as selective inhibitors of candida β-carbonic anhydrase enzyme.(2019-12-01) Akdemir, ATİLLA; ANGELI, A; GÖKTAŞ, F; Eraslan, Elma; KARALı, N; SUPURAN, CT; Inhibition of the b-carbonic anhydrase (CA, EC 4.2.1.1) from pathogenic Candida glabrata (CgNce103) by 1H-indole-2,3-dione 3-[N-(4-sulfamoylphenyl)thiosemicarbazones] 4a–m was investigated. All the compounds were found to be potent inhibitors of CgNce103, with inhibition constants in the range of 6.4- 63.9 nM. The 5,7-dichloro substituted derivative 4l showed the most effective inhibition (KI of 6.4 nM) as well as the highest selectivity for inhibiting CgNce103 over the cytosolic human (h) isoforms hCA I and II. A possible binding interaction of compound 4l within the active site of CgNce103 has been proposed based on docking studies.; AKDEMİR, ATİLLAInhibition of the b-carbonic anhydrase (CA, EC 4.2.1.1) from pathogenic Candida glabrata (CgNce103) by 1H-indole-2,3-dione 3-[N-(4-sulfamoylphenyl)thiosemicarbazones] 4a–m was investigated. All the compounds were found to be potent inhibitors of CgNce103, with inhibition constants in the range of 6.4- 63.9 nM. The 5,7-dichloro substituted derivative 4l showed the most effective inhibition (KI of 6.4 nM) as well as the highest selectivity for inhibiting CgNce103 over the cytosolic human (h) isoforms hCA I and II. A possible binding interaction of compound 4l within the active site of CgNce103 has been proposed based on docking studies.Publication Open Access Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold.(2019-12-01) De, Filippis; Rotondi, G; Guglielmi, P; De, Monte; Secci, D; Supuran, CT; Maccallini, C; Amoroso, R; Cirilli, R; Angeli, A; AKDEMİR, ATİLLAA large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.Publication Open Access Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms.(2017-12-01) D'ASCENZIO, M; GUGLIELMI, P; CARRADORI, S; SECCI, D; FLORIO, R; MOLLICA, A; CERUSO, M; Akdemir, ATİLLA; SOBOLEV, AP; SUPURAN, CT; AKDEMİR, ATİLLAA large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.Publication Open Access Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators(2017-12-01) Mollica, Adriano; Macedonio, Giorgia; Stefanucci, Azzurra; Carradori, Simone; Akdemir, ATİLLA; ANGELI, Andrea; Supuran, Claudiu T.; AKDEMİR, ATİLLAIt has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer’s disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 µM, whereas they were not active towards hCA II (KAs > 100 µM). Two natural compounds, namely L-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO2 hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site.